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1.
Bioorg Chem ; 99: 103846, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32334195

RESUMO

A base-mediated cascade reaction between malonate esters and acrolein was developed to access complex polycyclic systems. This novel tandem reaction enables the simultaneous generation of up to seven new bonds and at least three new stereogenic centers. Mechanistic studies indicate a series of nucleophilic 1,4 and 1,6 Michael addition reactions occur, followed by an aldol condensation reaction, culminating in the formation of three fused rings. The compounds were characterized by NMR studies and the stereochemistry was confirmed by X-ray analysis. The ability to generate multigram quantities of such complex molecular scaffolds renders the method promising for medicinal chemistry campaigns. Herein, we also demonstrate that the lead compounds display promising anti-proliferative activities against human cancer cell models.

2.
J Med Chem ; 62(15): 6925-6940, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31294974

RESUMO

The natural product colletoic acid (CA) is a selective inhibitor of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which primarily converts cortisone to the active glucocorticoid (GC) cortisol. Here, CA's mode of action and its potential as a chemical tool to study intracellular GC signaling in adipogenesis are disclosed. 11ß-HSD1 biochemical studies of CA indicated that its functional groups at C-1, C-4, and C-9 were important for enzymatic activity; an X-ray crystal structure of 11ß-HSD1 bound to CA at 2.6 Å resolution revealed the nature of those interactions, namely, a close-fitting and favorable interactions between the constrained CA spirocycle and the catalytic triad of 11ß-HSD1. Structure-activity relationship studies culminated in the development of a superior CA analogue with improved target engagement. Furthermore, we demonstrate that CA selectively inhibits preadipocyte differentiation through 11ß-HSD1 inhibition, suppressing other relevant key drivers of adipogenesis (i.e., PPARγ, PGC-1α), presumably by negatively modulating the glucocorticoid signaling pathway. The combined findings provide an in-depth evaluation of the mode of action of CA and its potential as a tool compound to study adipose tissue and its implications in metabolic syndrome.

3.
Molecules ; 24(10)2019 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-31130671

RESUMO

The increasing prevalence of drug resistant and/or high-risk cancers indicate further drug discovery research is required to improve patient outcome. This study outlines a simplified approach to identify lead compounds from natural products against several cancer cell lines, and provides the basis to better understand structure activity relationship of the natural product cephalotaxine. Using high-throughput screening, a natural product library containing fractions and pure compounds was interrogated for proliferation inhibition in acute lymphoblastic leukemia cellular models (SUP-B15 and KOPN-8). Initial hits were verified in control and counter screens, and those with EC50 values ranging from nanomolar to low micromolar were further characterized via mass spectrometry, NMR, and cytotoxicity measurements. Most of the active compounds were alkaloid natural products including cephalotaxine and homoharringtonine, which were validated as protein synthesis inhibitors with significant potency against several cancer cell lines. A generated BODIPY-cephalotaxine probe provides insight into the mode of action of cephalotaxine and further rationale for its weaker potency when compared to homoharringtonine. The steroidal natural products (ecdysone and muristerone A) also showed modest biological activity and protein synthesis inhibition. Altogether, these findings demonstrate that natural products continue to provide insight into structure and function of molecules with therapeutic potential against drug resistant cancer cell models.


Assuntos
Produtos Biológicos/farmacologia , Citostáticos/química , Citostáticos/farmacologia , Animais , Apoptose/efeitos dos fármacos , Produtos Biológicos/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas , Mepesuccinato de Omacetaxina/química , Mepesuccinato de Omacetaxina/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Relação Estrutura-Atividade
4.
J Nat Prod ; 82(5): 1301-1311, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31084028

RESUMO

Natural products continue to provide a platform to study biological systems. A bioguided study of cancer cell models led us to a new member of the jatrophane natural products from Jatropha gossypiifolia, which was independently identified and characterized as jatrogossone A (1). Purification and structure elucidation was performed by column chromatography and high-performance liquid chromatography-mass spectrometry and NMR techniques, and the structure was confirmed via X-ray crystallography. The unique molecular scaffold of jatrogossone A prompted an evaluation of its mode of action. Cytotoxicity assays demonstrated that jatrogossone A displays selective antiproliferative activity against cancer cell models in the low micromolar range with a therapeutic window. Jatrogossone A (1) affects mitochondrial membrane potential (ΔΨm) in a time- and dose-dependent manner. This natural product induces radical oxygen species (ROS) selectively in cancer cellular models, with minimal ROS induction in noncancerous cells. Compound 1 induces ROS in the mitochondria, as determined by colocalization studies, and it induces mitophagy. It promotes also in vitro cell death by causing cell arrest at the G2/M stage, caspase (3/7) activation, and PARP-1 cleavage. The combined findings provide a potential mechanism by which 1 relies on upregulation of mitochondrial ROS to potentiate cytotoxic effects through intracellular signaling.

5.
Org Biomol Chem ; 17(21): 5223-5229, 2019 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-31025693

RESUMO

Ergosterol peroxide selectively exhibits biological activity against a wide range of diseases; however, its mode of action remains unknown. Here, we present an efficient synthesis of ergosterol peroxide chemical probes for in vitro anticancer evaluation, live cell studies and proteomic profiling. Ergosterol peroxide analogues show promising anti-proliferation activity against triple negative breast cancer cellular models, revealing information on the structure-activity relationship of this natural product in order to develop superior analogues. The combined cellular studies demonstrate that ergosterol peroxide is distributed across the cytosol with significant accumulation in the endoplasmic reticulum (ER). These chemical probes support our efforts towards uncovering the potential target(s) of ergosterol peroxide against triple negative breast cancer cell lines.


Assuntos
Antineoplásicos/química , Ergosterol/análogos & derivados , Corantes Fluorescentes/química , Imagem Óptica , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ergosterol/síntese química , Ergosterol/química , Ergosterol/farmacologia , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Humanos , Microscopia de Fluorescência , Conformação Molecular , Neoplasias de Mama Triplo Negativas/patologia
6.
Front Pharmacol ; 10: 115, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30837881

RESUMO

We previously reported that Ganoderma lucidum extract (GLE) demonstrate significant anti-cancer activity against triple negative inflammatory breast cancer models. Herein, we aimed to elucidate the bioactive compounds of GLE responsible for this anti-cancer activity. We performed NMR, X-ray crystallography and analog derivatization as well as anti-cancer activity studies to elucidate and test the compounds. We report the structures of the seven most abundant GLE compounds and their selective efficacy against triple negative (TNBC) and inflammatory breast cancers (IBC) and other human cancer cell types (solid and blood malignancies) to illustrate their potential as anti-cancer agents. Three of the seven compounds (ergosterol, 5,6-dehydroergosterol and ergosterol peroxide) exhibited significant in vitro anti-cancer activities, while we report for the first time the structure elucidation of 5,6-dehydroergosterol from Ganoderma lucidum. We also show for the first time in TNBC/IBC cells that ergosterol peroxide (EP) displays anti-proliferative effects through G1 phase cell cycle arrest, apoptosis induction via caspase 3/7 activation, and PARP cleavage. EP decreased migratory and invasive effects of cancer cells while inhibiting the expression of total AKT1, AKT2, BCL-XL, Cyclin D1 and c-Myc in the tested IBC cells. Our investigation also indicates that these compounds induce reactive oxygen species, compromising cell fate. Furthermore, we generated a superior derivative, ergosterol peroxide sulfonamide, with improved potency in IBC cells and ample therapeutic index (TI > 10) compared to normal cells. The combined studies indicate that EP from Ganoderma lucidum extract is a promising molecular scaffold for further exploration as an anti-cancer agent.

7.
J Nat Prod ; 82(4): 823-831, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-30840453

RESUMO

The first semisynthesis and biological profiling of the new abietane diterpenoid (+)-liquiditerpenoic acid A (abietopinoic acid) (7) along with several analogues are reported. The compounds were obtained from readily available methyl dehydroabietate (8), which was derived from (-)-abietic acid (1). Biological comparison was conducted according to the different functional groups, leading to some basic structure-activity relationships (SAR). In particular, the ferruginol and sugiol analogues 7 and 10-16 were characterized by the presence of an acetylated phenolic moiety, an oxidized C-7 as a carbonyl, and a different functional group at C-18 (methoxycarbonyl, carboxylic acid, and hydroxymethyl). The biological properties of these compounds were investigated against a panel of six representative human tumor solid cells (A549, HBL-100, HeLa, SW1573, T-47D, and WiDr), five leukemia cellular models (NALM-06, KOPN-8, SUP-B15, UoCB1, and BCR-ABL), and four Leishmania species ( L. infantum, L. donovani, L. amazonensis, and L. guyanensis). A molecular docking study pointed out some targets in these Leishmania species. In addition, the ability of the compounds to modulate GABAA receptors (α1ß2γ2s) is also reported. The combined findings indicate that these abietane diterpenoids offer a source of novel bioactive molecules with promising pharmacological properties from cheap chiral-pool building blocks.

8.
Eur J Med Chem ; 164: 391-398, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30611980

RESUMO

Although pediatric leukemia is generally treatable, certain leukemic subtypes face poor prognosis in the clinic suggesting new selective therapeutic agents are needed. Thus, to identify selective apoptosis inducers, a small-molecule library screening approach was conducted using an isogenic leukemic murine p185+ B-ALL cell line pair (BCR-ABL-WT and the BAX/BAK deficient BCR-ABL-DKO). Gratifyingly, the investigation revealed several compounds featuring substituted aromatic five-membered-ring heterocycles with significant activity against murine and human leukemic cellular models. The identified compounds represent potentially novel antileukemic molecular scaffolds exemplified by compounds 1, 2 and 7, which demonstrated EC50 values in the nanomolar and low micromolar range against various leukemia subtypes (SUP-B15, KOPN-8, NALM-06, UoC-B1 cellular models) and pro-apoptotic properties in solid tumor cell models (MDA-MB-231, SUM149) with ample therapeutic index in normal cells. Herein, we highlight compounds 1, 2 and 7 which promote cell death mediated by caspase 3/7 induction. Our study establishes a strategic platform for the development of potent and selective anti-leukemic agents.


Assuntos
Antineoplásicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Leucemia/tratamento farmacológico , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspases/genética , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos/métodos , Indução Enzimática/efeitos dos fármacos , Compostos Heterocíclicos/química , Humanos , Camundongos , Bibliotecas de Moléculas Pequenas/uso terapêutico , Índice Terapêutico
9.
Mol Inform ; 38(3): e1800080, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30369061

RESUMO

Histone Deacetylases (HDACs) are an important family of 18 isozymes, which are being pursued as drug targets for many types of disorders. HDAC2 and HDAC8 are two of the isozymes, which have been identified as drug targets for the design of anti-cancer, neurodegenerative, immunological, and anti-parasitic agents. Design of potent HDAC2 and HDAC8 inhibitors will be useful for the therapeutic advances in many disorders. This work was undertaken to develop potent HDAC2 and HDAC8 inhibitors. A docking study was performed comparing panobinostat derivatives in both HDAC2 and HDAC8. Six of our derivatives showed stronger binding to HDAC2 than panobinostat, and two of our derivatives showed stronger binding to HDAC8 than panobinostat. We evaluated the molecular features, which improved potency of our inhibitors over panobinostat and also identified another molecular consideration, which could be used to enhance histone deacetylase inhibitor (HDACi) selectivity towards either the HDAC2 or HDAC8 isozymes. The results of this work can be used to assist future design of more potent and selective HDACi for HDAC2 and HDAC8.


Assuntos
Desenho de Fármacos , Histona Desacetilase 2/química , Inibidores de Histona Desacetilases/química , Histona Desacetilases/química , Simulação de Acoplamento Molecular , Panobinostat/análogos & derivados , Proteínas Repressoras/química , Sítios de Ligação , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Humanos , Ligação Proteica , Proteínas Repressoras/metabolismo , Especificidade por Substrato
11.
Eur J Med Chem ; 146: 501-510, 2018 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-29407975

RESUMO

Acute lymphoblastic leukemia (ALL) is the most common type of leukemia in children. Up to a quarter of ALL patients relapse and face poor prognosis. To identify new compound leads, we conducted a phenotypic screen using terrestrial natural product (NP) fractions against immortalized ALL cellular models. We identified vitexin, a flavonoid, as a promising hit with biological activity (EC50 = 30 µM) in pre-B cell ALL models with no toxicity against normal human tissue (BJ cells) at the tested concentrations. To develop more potent compounds against ALL and elucidate its potential mode of action, a vitexin-inspired compound library was synthesized. Thus, we developed an improved and scalable protocol for the direct synthesis of 4-quinolone core heterocycles containing an N-sulfonamide using a one-pot condensation reaction protocol. The newly generated compounds represent a novel molecular scaffold against ALL as exemplified by compounds 13 and 15, which demonstrated EC50 values in the low micromolar range (0.3-10 µM) with little to no toxicity in normal cellular models. Computational studies support the hypothesis that these compounds are potential CDK inhibitors. The compounds induced apoptosis, caused cell arrest at G0/G1 and G2/M, and induced ROS in cancer cells.


Assuntos
Apigenina/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Apigenina/síntese química , Apigenina/química , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Relação Estrutura-Atividade
12.
PLoS One ; 12(12): e0189864, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29281678

RESUMO

Metastatic breast cancer is the leading cause of worldwide cancer-related deaths among women. Triple negative breast cancers (TNBC) are highly metastatic and are devoid of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) amplification. TNBCs are unresponsive to Herceptin and/or anti-estrogen therapies and too often become highly chemoresistant when exposed to standard chemotherapy. TNBCs frequently metastasize to the lung and brain. We have previously shown that TNBCs are active for oncogenic Wnt10b/ß-catenin signaling and that WNT10B ligand and its downstream target HMGA2 are predictive of poorer outcomes and are strongly associated with chemoresistant TNBC metastatic disease. In search of new chemicals to target the oncogenic WNT10B/ß-CATENIN/HMGA2 signaling axis, the anti-proliferative activity of the diterpene Jatrophone (JA), derived from the plant Jatropha isabelli, was tested on TNBC cells. JA interfered with the WNT TOPFLASH reporter at the level between receptor complex and ß-catenin activation. JA efficacy was determined in various subtypes of TNBC conventional cell lines or in TNBC cell lines derived from TNBC PDX tumors. The differential IC50 (DCI50) responsiveness was compared among the TNBC models based on etiological-subtype and their cellular chemoresistance status. Elevated WNT10B expression also coincided with increased resistance to JA exposure in several metastatic cell lines. JA interfered with cell cycle progression, and induced loss of expression of the canonical Wnt-direct targets genes AXIN2, HMGA2, MYC, PCNA and CCND1. Mechanistically, JA reduced steady-state, non-phosphorylated (activated) ß-catenin protein levels, but not total ß-catenin levels. JA also caused the loss of expression of key EMT markers and significantly impaired wound healing in scratch assays, suggesting a direct role for JA inhibiting migration of TNBC cells. These results indicate that Jatrophone could be a powerful new chemotherapeutic agent against highly chemoresistant triple negative breast cancers by targeting the oncogenic Wnt10b/ß-catenin signaling pathway.


Assuntos
Proliferação de Células/efeitos dos fármacos , Diterpenos/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/patologia , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Neoplasias de Mama Triplo Negativas/metabolismo
13.
Eur J Med Chem ; 113: 75-80, 2016 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-26922230

RESUMO

The cure rate of pediatric acute lymphoblastic leukemia (ALL) has significantly improved in the past thirty years, however not all patient cohorts respond well to current chemotherapy regimens. Among the high risk patient cohort is infants with MLL-rearranged (MLL-r) B-ALL, which remains dismal with an overall survival rate <35%. Our program is interested in identifying new molecular scaffolds to better understand the underlying mechanisms and ultimately provide new targeted treatments. Based on a phenotypic screen, phenolic natural products were identified as promising scaffolds for further chemical evaluation. Herein we disclose the effects of a potent anti-proliferative compound 31 against human ALL leukemia cellular models.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Monoterpenos/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Monoterpenos/síntese química , Monoterpenos/química , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Relação Estrutura-Atividade
14.
Eur J Med Chem ; 110: 126-32, 2016 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-26820555

RESUMO

Cortisol homeostasis has been linked to the pathogenesis of metabolic syndrome (MetS), since it stimulates hepatic gluconeogenesis and adipogenesis. MetS is classified as a constellation of health conditions that increase the risk of type 2 diabetes and cardiovascular disease. Intracellular cortisol levels are regulated by 11ß-hydroxysteroid dehydrogenase (type 1 and type 2) in a tissue dependent manner. The type 1 enzyme (11ß-HSD1) is widely expressed in glucocorticoid targeted tissues and is responsible for the conversion of cortisone to the active cortisol. Local reduction of cortisol regeneration presents a potential strategy for MetS treatment. Recently we disclosed the total synthesis of (+)-colletoic acid as a potent 11ß-HSD1 inhibitor. Herein, we describe our improved processing chemistry for the synthesis of the colletoic acid core to access a diverse number of derivatives for evaluation against 11ß-HSD1. The Evan's chiral auxiliary was utilized to construct the acyclic precursor 12 to afford the acorane core 9 using a modified Heck reaction in excellent chemical yields. The colletoic acid core derivatives showed modest activity against 11ß-HSD1 and will serve for further biological evaluation.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hidrocortisona/metabolismo , Sesquiterpenos/química , Sesquiterpenos/farmacologia , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Inibidores Enzimáticos/síntese química , Humanos , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/enzimologia , Síndrome Metabólica/metabolismo , Modelos Moleculares , Sesquiterpenos/síntese química
15.
Eur J Med Chem ; 102: 9-13, 2015 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-26241873

RESUMO

Breast cancer remains the leading cause of cancer-related death among women. The invasive triple-negative subtype is unresponsive to estrogen therapy, and few effective treatments are available. In search of new chemical scaffolds to target this disease, we conducted a phenotypic screen against the human breast carcinoma cell lines MDA-MB-231, MA11, and MCF-7 using terrestrial natural products. Natural products that preferentially inhibited proliferation of triple-negative MDA-MB-231 cells over estrogen receptor-positive cells were further studied; herein we focused on the abietanes. The activity of the abietane carnosol prompted us to generate a focus library from the readily available (+)-dehydroabietylamine. The lead compound 61 displayed a promising EC50 of 9.0 µM against MDA-MB-231 and our mechanistic studies indicate it induced apoptosis, which was associated with activation of caspase-9 and -3 and the cleavage of PARP. Here we describe our current progress towards this promising therapeutic candidate.


Assuntos
Abietanos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Produtos Biológicos/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Abietanos/química , Abietanos/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Apoptose/efeitos dos fármacos , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Células MCF-7 , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade , Neoplasias de Mama Triplo Negativas/patologia
16.
Blood Press Monit ; 20(4): 232-6, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25856419

RESUMO

When home blood pressure (HBP) measurements are taken, the readings can be registered manually by the patient and/or stored in the device's memory. The instructions provided by healthcare professionals would be particularly relevant to guarantee the reliability of manual blood pressure (BP) figures and enhance clinical decision making. The aim of this study is assess the agreement between HBP measurements manually registered by patients and those stored in the device's memory after an educational session provided by community pharmacists. Secondary data of the MEPAFAR and the Palmera studies have been used in this analysis. All the (treated hypertensive) patients attended an individual educational session in which they were instructed on how to use the measurement device and properly measure and manually register HBP. The same device and HBP monitoring protocol were used in both studies: 4 consecutive days (three morning measurements and three in the evening). HBP measurements were both manually registered by patients and stored in the device's memory. To evaluate the agreement between BP figures, Lin's correlation-concordance coefficient and κ coefficient were used for quantitative and qualitative agreement, respectively. One hundred and sixty-sixty patients were included in this analysis. The agreement between the average manual and the stored HBP was very good [systolic=0.99, 95% confidence interval (CI): 0.99-0.99; diastolic=0.99, 95% CI: 0.99-1.00]. 99.4% of patients were classified in the same category by both alternatives [κ index=0.99 (95% CI: 0.98-1.00)]. In this sample of treated hypertensive patients, the agreement between manually registered and stored BP figures was very good. This high concordance may be explained by the pharmacist's intervention.


Assuntos
Monitorização Ambulatorial da Pressão Arterial , Monitores de Pressão Arterial , Educação de Pacientes como Assunto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Farmácias
17.
Bioorg Med Chem Lett ; 24(22): 5234-7, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25316317

RESUMO

The abietane-type diterpenoid (+)-ferruginol, a bioactive compound isolated from New Zealand's Miro tree (Podocarpus ferruginea), displays relevant pharmacological properties, including antimicrobial, cardioprotective, anti-oxidative, anti-plasmodial, leishmanicidal, anti-ulcerogenic, anti-inflammatory and anticancer. Herein, we demonstrate that ferruginol (1) and some phthalimide containing analogues 2-12 have potential antimalarial activity. The compounds were evaluated against malaria strains 3D7 and K1, and cytotoxicity was measured against a mammalian cell line panel. A promising lead, compound 3, showed potent activity with an EC50 = 86 nM (3D7 strain), 201 nM (K1 strain) and low cytotoxicity in mammalian cells (SI>290). Some structure-activity relationships have been identified for the antimalarial activity in these abietane analogues.


Assuntos
Abietanos/química , Antimaláricos/química , Ftalimidas/química , Extratos Vegetais/química , Abietanos/isolamento & purificação , Abietanos/farmacologia , Animais , Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Células CHO , Cricetinae , Cricetulus , Células Hep G2 , Humanos , Ftalimidas/isolamento & purificação , Ftalimidas/farmacologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/fisiologia
18.
Molecules ; 19(1): 756-66, 2014 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-24406786

RESUMO

Over 216 million malaria cases are reported annually worldwide and about a third of these cases, primarily children under the age of five years old, will not survive the infection. Despite this significant world health impact, only a limited number of therapeutic agents are currently available. The lack of scaffold diversity poses a threat in the event that multi-drug-resistant strains emerge. Terrestrial natural products have provided a major source of chemical diversity for starting materials in many FDA approved drugs over the past century. Bixa orellana L. is a popular plant used in South America for the treatment of malaria. In search of new potential therapeutic agents, the chemical constituents of a selected hairy root culture line of Bixa orellana L. were characterized utilizing NMR and mass spectrometry methods, followed by its biological evaluation against malaria strains 3D7 and K1. The crude extract and its isolated compounds demonstrated EC50 values in the micromolar range. Herein, we report our findings on the chemical constituents of Bixa orellana L. from hairy roots responsible for the observed antimalarial activity.


Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Bixaceae/química , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Antimaláricos/toxicidade , Linhagem Celular , Ciclopentanos/química , Humanos , Isomerismo , Estrutura Molecular , Oxilipinas/química , Testes de Sensibilidade Parasitária , Extratos Vegetais/toxicidade
19.
Org Lett ; 15(22): 5790-3, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24175735

RESUMO

An efficient and divergent total synthesis of (+)-colletoic acid, a selective 11-ß hydroxysteroid dehydrogenase 1 (11-ßHSD1) inhibitor, is presented along with its biological activity at the whole-cell level. A scalable, asymmetric synthetic strategy was designed featuring a diversity-oriented synthesis utilizing a diastereoselective intramolecular 5-exo-Heck reaction as the key step to provide the quaternary spirocenter intermediate 9 in multigram scale, thus establishing a platform for further structure-activity relationship studies and providing access to other acorane family members.


Assuntos
11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/química , Sesquiterpenos/síntese química , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Estrutura Molecular , Sesquiterpenos/química , Estereoisomerismo , Relação Estrutura-Atividade
20.
Eur J Med Chem ; 65: 376-80, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23747806

RESUMO

Protozoal diseases such as malaria are a leading world health concern. We screened a library of fractionated natural products to identify new potential therapeutic leads and discovered that jatrophone (a product of Jatropha isabelli) exerts significant activity against Plasmodium falciparum strains 3D7 and K1. A focused jatrophone-scaffold library was synthesized to evaluate jatrophone's mode of action and identify more selective analogs. Compounds 25 and 32 of this natural product-inspired compound library exhibited micromolar EC50 values against strains 3D7 and K1, thus providing a new antimalarial molecular scaffold. Our report describes an efficient derivatization approach used to evaluate the structure-activity relationship of jatrophone analogs in search of potential new antimalarial agents.


Assuntos
Antiprotozoários/farmacologia , Produtos Biológicos/farmacologia , Jatropha/química , Plasmodium falciparum/efeitos dos fármacos , Antiprotozoários/química , Antiprotozoários/isolamento & purificação , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Relação Dose-Resposta a Droga , Conformação Molecular , Testes de Sensibilidade Parasitária , Estereoisomerismo , Relação Estrutura-Atividade
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